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TP53 bound to a short DNA fragment. Protein atoms are represented as sticks, the DNA helix is in spacefill mode. Click for larger image.
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TP53 bound to a short DNA fragment. Protein atoms are represented as sticks, the DNA helix is in spacefill mode. Click for larger image.

p53, also known as tumor protein 53 (TP53), is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor. It is very important for cells in multicellular organisms to suppress cancer. TP53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation [6]. The name is due to its molecular mass: it runs as a 53 kilodalton (kDa) protein on SDS-PAGE. Tumor Suppressor P53 Complexed With DNA. Image made from 1tup. ... Tumor Suppressor P53 Complexed With DNA. Image made from 1tup. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ... The cell cycle, or cell division cycle, is the cycle of events in a eukaryotic cell from one cell division to the next. ... A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. ... Multicellular organisms are those organisms consisting of more than one cell, and having differentiated cells that perform specialized functions. ... When normal cells are damaged beyond repair, they are eliminated by apoptosis. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... The molecular mass (abbreviated MM) of a substance, called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... The atomic mass unit (amu), unified atomic mass unit (u), or dalton (Da), is a small unit of mass used to express atomic masses and molecular masses. ... Picture of an SDS-PAGE. The molecular marker is in the left lane SDS-PAGE stands for Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis. ...

Contents


Names of Protein

  • Official protein name: Cellular tumor antigen p53

Synonyms:

  • Tumor suppressor p53
  • Phosphoprotein p53
  • Antigen NY-CO-13

Gene

The human TP53 gene, TP53, is located on the human chromosome 17 (17p13.1). TP53 (tumor protein p53 (Li-Fraumeni syndrome)) is a gene that provides instructions for making a protein called tumor protein p53. ... Chromosome 17 is one of the 23 pairs of chromosomes in humans. ...


The location has also been mapped on other model animals:

  • Mouse - chromosome 11
  • Rat - chromosome 10
  • Dog - chromosome 5
  • Pig - chromosome 12

Binomial name Mus musculus Linnaeus, 1758 Mus musculus is the common house mouse. ... Binomial name Rattus norvegicus (Berkenhout, 1769) The Brown Rat or Norway Rat (Rattus norvegicus) is one of the most well-known and common rats, and also one of the largest. ... Trinomial name Canis lupus familiaris (Linnaeus, 1758) This article is about the domestic dog. ... Species Sus barbatus Sus bucculentus Sus cebifrons Sus celebensis Sus domesticus Sus heureni Sus philippensis Sus salvanius Sus scrofa Sus timoriensis Sus verrucosus Pigs are ungulates native to Eurasia collectively grouped under the genus Sus within the Suidae family. ...

Structure

TP53 is 393 amino acids long and has three domains: In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ...

  • A domain that activates transcription factors.
  • A domain that recognizes specific DNA sequences (core domain). Mutations which deactivate p53 in cancer usually occur here. Contains zinc molecules.
  • A domain that is responsible for the tetramerization of the protein. Tetramerization greatly increases the activity of p53 in vivo.

Wild-type TP53 is a labile protein, comprising folded and unstructured regions which function in a synergistic manner [2]. In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ... For other uses, see DNA (disambiguation). ...


Functional Significance

p53 has many anti-cancer mechanisms:

  • It can activate DNA repair proteins when DNA has sustained damage.
  • It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition.
  • It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irrepairable.

p53 is central to many of the cell's anti-cancer mechanisms. It can induce growth arrest, apoptosis and cell senescence. In normal cells p53 is usually inactive, bound to the protein MDM2, which prevents its action and promotes its degradation by acting as ubiquitin ligase. Active p53 is induced after the effects of various cancer-causing agents such as UV radiation, oncogenes and some DNA-damaging drugs. DNA damage is sensed by 'checkpoints' in a cell's cycle, and causes proteins such as ATM, CHK1 and CHK2 to phosphorylate p53 at sites that are close to or within the MDM2-binding region of the protein. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. Some oncogenes can also stimulate the transcription of proteins which bind to MDM2 and inhibit its activity. Once activated p53 transcribes several genes including one for p21. p21 binds to the G1-S/Cdk and S/Cdk complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. p53 has many anticancer mechanisms, and plays a role in apoptosis, genetic stability, and inhibition of angiogenesis [7]. DNA damage resulting in multiple broken chromosomes DNA repair is a process constantly operating in cells; it is essential to survival because it protects the genome from damage and harmful mutations. ... The cell cycle, or cell division cycle, is the cycle of events in a eukaryotic cell from one cell division to the next. ... Apoptosis In biology, apoptosis (from the Greek words apo = from and ptosis = falling, commonly pronounced ap-a-tow-sis[1]) is one of the main types of programmed cell death (PCD). ... Apoptosis In biology, apoptosis (from the Greek words apo = from and ptosis = falling, commonly pronounced ap-a-tow-sis[1]) is one of the main types of programmed cell death (PCD). ... In biology, senescence is the combination of processes of deterioration which follow the period of development of an organism. ... mdm2 is an E3 ubiquitin ligase that recognizes the N-terminal activation domain (TAD) of the p53 transcription factor. ... Note: Ultraviolet is also the name of a 1998 UK television miniseries about vampires. ... An oncogene is a modified gene that increases the malignancy of a tumor cell. ... Ataxia-telangiectasia mutated kinase is a serine threonine kinase that is recruited and activated by double stranded breaks of DNA and the MRN complex. ...


Recent research has also linked the p53 and RB1 [1] pathways, via p14ARF, raising the possibility that the pathways may regulate each other [1]. The Retinoblastoma protein, or pRb, is a tumor suppressor protein found to be dysfunctional in a number of types of cancer. ...


Role in disease

If TP53 is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of TP53 will most likely develop tumors in early adulthood, a disease known as Li-Fraumeni syndrome. TP53 can also be damaged in cells by mutagens (chemicals, radiation or viruses), increasing the likelihood that the cell will begin uncontrolled division. More than 50 percent of human tumors contain a mutation or deletion of TP53. Li-Fraumeni syndrome is a rare autosomal dominant hereditary disorder. ... In biology, a mutagen (Latin, literally origin of change) is an agent that changes the genetic information (usually DNA) of an organism and thus increases the number of mutations above the natural background level. ... A chemical substance is any material substance used in or obtained by a process in chemistry: A chemical compound is a substance consisting of two or more chemical elements that are chemically combined in fixed proportions. ... Radiation has a variety of different meanings. ... The human immunodeficiency virus (HIV) A bacteriophage virus A virus is a submicroscopic parasitic particle that infects cells in biological organisms. ... This article is about modern humans. ... Tumor (American English) or tumour (British English) originally means swelling, and is sometimes still used with that meaning. ... In biology, mutations are changes to the genetic material (usually DNA or RNA). ... A gene deletion, or deletion mutation is a genetic mutation in which a part of a chromosome or a sequence of DNA is missing. ...


Certain pathogens can also affect p53. One such example, the Human papillomavirus (HPV), encodes for a protein, E6, which binds p53 and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, p105RB, allows for repeated cell division manifestested in the clinical disease of warts. Human papillomavirus (HPV)is a member of a group of viruses known as the genus Papillomavirus that can infect humans and cause changes in cells leading to abnormal tissue growth. ... A wart is a generally small, rough, cauliflower-like growth, typically on hands and feet. ...


In health p53 is continually produced and degraded in the cell. The degradation of p53 is, as mentioned, associated with MDM2 binding. In a negative feedback loop MDM2 is itself induced by p53. However mutant p53s often don't induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 itself can inhibit normal p53 [4].


Potential therapeutic use

In-vitro introduction of p53 in to p53-deficient cells has been shown to cause rapid death of cancer cells or prevention of further division. It is these more acute effects which hopes rest upon therapeutically [5]. The rationale for developing therapeutics targeting p53 is that "the most effective way of destroying a network is to attack its most connected nodes". p53 is extremely well connected (in network terminology it is a hub) and knocking it out cripples the normal functioning of the cell. This can be seen as 50% of cancers have missense point mutations in TP53, these mutations impair its anti-cancer gene inducing effects. Restoring its function would be a major step in curing many cancers [7].


Various strategies have been proposed to restore p53 function in cancer cells [4]. A number of groups have found molecules which appear to restore proper tumour suppressor activity of p53 in vitro. These work by altering the conformation of mutant conformation of p53 back to an active form. So far, no molecules have shown to induce biological responses, but some may be lead compounds for more biologically active agents. A promising target for anti-cancer drugs is the molecular chaperone Hsp90, which interacts with p53 in vivo. The molecular chaperone Hsp90 is one of the most abundant proteins in unstressed cells. ...


Adenoviruses have been used to study the functions of p53 by scientists for years, but in a twist it is now modified adenoviruses which are being used as new cancer therapy tools. ONYX-O15 (dl1520, H101, CI-1042) is a modified adenovirus which was initially proposed selectively replicate in TP53-deficient cancer cells, but not normal cells [3]. The wild form of the virus expresses the early region protein, E1B55kDa, which binds to and inactivates p53 - this inactivation is necessary for the virus to replicate and kill, or lyse, a cell. In ONYX-O15, E1B55kDa has been deleted. It was hoped that in cells with a normal p53, ONYX-O15 would be disabled by p53's activity, yet in cells with a dysfunctional p53, ONYX-O15 would selectively replicate in and lyse the tumour cells. The virus produced from this replication cycle could then spread to other surrounding malignant tissue and, over many cycles of infection, replication and lysis, eventually clear the tumour cells from the patient.


Preclinical trials using the ONYX-O15 virus on mice were promising. However, the clinical trials that followed were less so. Furthermore, many other scientists have since found that the virus is able replicate in cells with wild-type p53 as effectively as in cells with dysfunctional p53. Nevertheless, when the virus was used in combination with chemotherapy the results looked encouraging [5]. Following on from this the virus has now been liscenced for therapeutic use in China. Without a complete understanding of exactly how the virus is selective for cancer cells the virus is unlikely to be used as a therapeutic in western countries.


Importantly, normal p53 is exploited in radiation therapy. Cells with healthy expression of p53 apoptose (undergo programmed cell death) in the presence of irreparable damage to the DNA. By inducing double-strand DNA damage using theraputic radiation, p53-mediated apoptosis can be elicited. In cells properly expressing p53, this pathway can be a powerful tool in the battle with neoplastic disease. Neoplasia (literally: new growth) is abnormal, disorganized growth in a tissue or organ, usually forming a distinct mass. ...


History

TP53 was identified in 1979 by Arnold Levine, David Lane, and Lloyd Old, working at Princeton University, Imperial Cancer Research Fund (UK), and Sloan-Kettering Memorial Hospital, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The p53 gene was first cloned in 1983 by Moshe Oren (Weizmann Institute). This page refers to the year 1979. ... Princeton University, incorporated as The Trustees of Princeton University, located in Princeton, New Jersey, is the fourth-oldest institution to conduct higher education in the United States. ... The Imperial Cancer Research Fund was a cancer research organization in the United Kingdom. ... SV40 is an abbreviation for Simian vacuolating virus 40 or Simian virus 40, a polyomavirus that is found in both monkeys and humans. ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... The Weizmann Institute of Science (מכון ויצמן למדע) is an institute of higher learning and research in Rehovot, Israel. ...


It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989. An oncogene is a modified gene that increases the malignancy of a tumor cell. ... In genetics, complementary DNA (cDNA) is single-stranded DNA synthesized from a mature mRNA template. ... The interaction of mRNA in a eukaryote cell. ... 1989 (MCMLXXXIX) was a common year starting on Sunday of the Gregorian calendar. ...


In 1993, p53 was voted molecule of the year by Science magazine. 1993 (MCMXCIII) was a common year starting on Friday of the Gregorian calendar and marked the Beginning of the International Decade to Combat Racism and Racial Discrimination (1993-2003). ... Science is the journal of the American Association for the Advancement of Science (AAAS). ...


External links

  • Structure of p53
  • Molecule of the year
  • OMIM 191170
  • Swissprot: Cellular tumor antigen p53
  • TP53 at the GenAge database.
  • Entrez Gene: TP53
  • The p53 Knowledgebase

The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ...

References

  1. p14ARF links the tumour suppressors RB and p53. Nature. 1998 Sep 10; 395(6698): 124-5;
  2. p53 contains large unstructured regions in its native state. J Mol Biol. 2002 Oct 4; 322(5): 917-27; Abstract
  3. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science. 1996 Oct 18; 274(5286): 373-6; Abstract
  4. P53: an ubiquitous target of anticancer drugs. Int J Cancer. 2002 Mar 10; 98(2): 161-6; Abstract
  5. Cancer gene therapy: fringe or cutting edge? Nat Rev Cancer. 2001 Nov; 1(2): 130-41; Abstract
  6. Strachan T, Read AP. (1999). Human Molecular Genetics 2. Ch. 18, Cancer Genetics
  7. Surfing the p53 network. Nature. 2000 Nov 16; 408(6810): 307-10; Abstract

  Results from FactBites:
 
P53 - Wikipedia, the free encyclopedia (1239 words)
p53, also known as tumor protein 53 (TP53), is a transcription factor that regulates the cell cycle and hence functions as a tumor suppressor.
Tetramerization greatly increases the activity of p53 in vivo.
The p53 gene was first cloned in 1983 by Moshe Oren (Weizmann Institute).
  More results at FactBites »

 
 

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